We propose to address a series of dietary and hormonal hypothesis related to colorectal neoplasia in the Health Professionals Follow-Up Study (HPFS) and Nurses? Health Study (NHS) Cohorts. Participants for the analysis of cancers will be drawn from the HPFS whereas participants for the analysis of adenomas will be drawn from both cohorts. We expect 1126 incident cases of colorectal cancer among the HPFS with prospectively collected dietary data, whereas we expect 4,548 total adenomas and 1,494 adenomas less than 1 cm from both cohorts. The repeated measures of diet and other exposures will allow an assessment of long-term patterns as well as the impact of changes in diet and other exposures. We propose to build upon, extend, and refine observations we have already made on the dietary and hormonal influences of colorectal neoplasia. We propose to focus on 5 areas: (1) nutritional influences on DNA synthesis, methylation, and repair; (2) external (including dietary) carcinogen; (3) physical activity, body mass index, weight gain; and tumor promoting growth factor; (4) non-steroidal ani-inflammatory drugs (NSAIDs) that inhibit cyclo-oxygenase-2 (COX-2); and (5) calcium and vitamin D receptor polymorphisms. We propose to develop each of these areas through questionnaires over a 18-year period to better assess the impact of long-term exposures, to account for various induction periods, and to examine for the impact of change. We will also examine how hormones may underlie the basis of action for physical activity, body mass in index, and weight change, and we will extra DNA from blood and buccal samples to examine hypothesized gene-environment interactions. In addition, we propose to acquire and use paraffin-embedded tissue specimens to examine how etiologic factors correlate with specific well-established molecular alterations (including the prevalence and spectrum K-ras mutations, level of microsatellite instability, prevalence of hMLH1 hypermethylation, and the levels of p53, p27, and COX-2 expression) in colorectal neoplasia. These studies are aimed to enhance our understanding of colorectal carcinogenesis and to provide a firm scientific foundation for future preventive efforts.